The thyroid hormones thyroxine (T4) and triiodothyronine (T3) play a significant role in the growth, development and differentiation of normal cells. Thyroxine (3,5,3′,5′-tetraiodothyronine, T4), is the major hormone secreted by the follicular cells of the thyroid gland. Triiodothyronine, (T3) is a thyroid hormone similar to T4 but with one fewer iodine atoms per molecule. Thyroid-stimulating hormone (TSH), secreted from the hypophisis, controls the production of T4 and T3. In the thyroid, T4 is converted to T3, however, most of the circulating T3 is formed peripherally by deiodination of T4 (85%). Thus, T4 acts as prohormone for T3.
T4 is the standard thyroid hormone used for replacement therapy in patients with hypothyroidism [1]. T4 in combination with T3 for treatment of clinical hypothyroidism was reviewed [2]. T4 in combination with T3 or T4 alone have also been used to treat various mood disorders such as unipolar depression [3] and major depression. T3 alone (at daily doses of 25-50 μg for 4 weeks) was found to be effective in treating depression in patients non-responsive to serotonin selective reuptake inhibitors [4]. Further, T3 (20-25 μg per day for 1 week; 40-50 μg/day thereafter) was combined with Sertalin to treat depression [5].
Excess of thyroid hormones (i.e. hyperthyroidism) resulting in an excess of circulating free T4 and T3 or both, which is a mark of Grave's disease, can be treated by using anti-thyroid drugs such as propylthiouracil (PTU) and methimazole [6].
Current research points to a link between the level of thyroid hormone and the risk for developing cancer. Clinical studies, in addition to animal studies have suggested that thyroid hormones may positively modulate neoplastic cells. On the other hand, it was postulated that lowering the levels of thyroid hormones (i.e. by introducing a hypothyroid state) can lead to decreased tumorgenicity and increased survival. For example, Hercbergs and Leith reported on a patient suffering from metastatic lung cancer in which spontaneous remission of his cancer was documented, following a myxedema coma episode (extremely low levels of thyroid hormones) [7].
Hellevik A I et al. showed that TSH levels suggestive of hyperthyroid function were associated with increased risk of cancer [8]. Kumar M S, et al. also showed, using an animal model, that T4 stimulates tumor growth and metastasis [9].
Rosenberg A G et al. suggested an epidemiologic link between thyroid dysfunction and renal cell carcinoma [10].
Nelson M, et al. Reported improved survival in hypothyroid head and neck cancer patients and hypothesized that maintaining patient at a clinically tolerable level of hypothyroidism may have a beneficial effect in regard to their neoplastic disease [11].
Cristofanilli M, et al. pointed to a reduced risk and significantly older age at onset/diagnosis of primary breast carcinoma in patients suffering from primary hypothyroidism [12].
Theodossiou C, et al. indicates that human lung and prostate tumors do not grow well in hypothyroid nude mice. [13].
Mendeleyev J, et al. described a method of treating a malignant tumor using a T4 analogue having no significant hormonal activity [14].
Hercbergs A, et al. describe that propylthiouracil-induced chemical hypothyroidism with high dose tamoxifen prolonged survival in recurrent high grade glioma. [15]. Hercbergs A also found a highly significant correlation between a free thyroxine decline below the reference range and the six month progression free survival [16].
Japanese patent application No. 63-79824 [17] describes carcinostatic agents comprising as active ingredients iodotyrosine, such as monoiodotyrosine (MIT) and diiodotyrosine (DIT); and/or iodothyronine, such as triiodothyronine (T3) and iodothyroxinee (T4). The dosage range described for MIT and DIT is 10 mg to 10 g/day per 50 kg body weight, to be administered by intravenous injection or orally; and with regard to T3 and T4, administration includes IV injection in the range from 1 μg to 1 mg/day per 50 kg body weight, preferably using both in dosages from 0.1 mg/day per 50 kg body weight to 25 μg/day, and even more preferably oral administration of tyrosine and iodine in dosages of 10 mg to 10 g/day per 50 kg body weight.
T3 and more potently, T4 affects cell division and angiogenesis through binding to integrin αVβ3, commonly overexpressed on many cancer cells [18]. Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells [19].